IE45365B1 - Homocysteine thiolactone derivatives - Google Patents
Homocysteine thiolactone derivativesInfo
- Publication number
- IE45365B1 IE45365B1 IE1645/77A IE164577A IE45365B1 IE 45365 B1 IE45365 B1 IE 45365B1 IE 1645/77 A IE1645/77 A IE 1645/77A IE 164577 A IE164577 A IE 164577A IE 45365 B1 IE45365 B1 IE 45365B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- homocysteine thiolactone
- compounds
- hydrochloride
- homocysteine
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pyridine Compounds (AREA)
Abstract
N-6-chloronicotinoyl-d,l-homocysteine thiolactone of the formula (1) and method for its preparation are described. The compound has antilipolytic activity and is useful in compositions for treatment of conditions of elevated free fatty acid and triglyceride plasma levels.
Description
This invention provides ST - 6 - chloronicotinoyl - d, 1hosnocysteine thio lactone having the formula I;
and its pharmacologically acceptable salts, a process for the preparation of the compound and its salts, and pharmaceutical compositions comprising the compound or its salt and a pharmaceutical carrier. Compound (I) may be used as such or as a salt with mineral acids, e.g. hydrochloric, sulphuric, anr with mono - or poly10 carboxylic aliphatic organic acids, e.g., formic, ace.tie, tartan c lactic, succinic, malonic, glutaric, adipic, / , citric, malic, maleic and funiaric acids, or with aromatic acids such as benzoic, salicylic, . and pamoic acids, or with mandelie, diphenylacetic, and benzyl ic acids, or with sulfonic acids such as msthanesulfonic, bensenesulfonic, and toluene sulfonic acids, or with sulfamic acids such as cyelamic acid, . Compound (Ϊ) and some pharmacologically acceptable salts v/hich have been tested have shewn important pharmacological properties, particularly low toxicity, high anti-lipolitic and good liver protecting activity.
K - 6 - chloronicotinoyl - d, 1 - homocysteine thiolac45365 tone may be prepared, with high yield, by making 6 - chloroacid nicotinic/chloride hydrochloride react with homocysteine thiolactone hydrochloride (generally 6 - chloronicotinic acid chloride hydrochloride is prepared by reacting thionyl chloride with 6 - chloronicotinic acid without solvents) in the presence of an excess of pyridine or another tertiary organic basic compound di.v? rived in an inert nen-aqueous organic solvent (preferabii anhydrousί , e.g. chloroform or dioxane. The reaction takes place at room temperature, .is generally exothe**c rinie and reaches, without cooling, oO—60 C.
The reaction is ccmn.'ete in about 2 hours. The mixture resulting from the reaction in cooled and washed several times with H O, than the «wt is evaporated in vacuo and the solid thus obtain->d .:-: generally purified by dissolving the precipitate in EtCfi, decolorizing with active charcoal upon boiling, coolis, sc-5 adding purified water. The resulting solid is the : i.usc (1) which may bs salified by means of the above v-hs.
S - 6 -· rh.. oronicof irsoyl - d. 1 - homocysteine thiolactone is a whits microcrystailine powder stable to heat and light. Compound (Ϊ) sad its salts may be administered both as such and togeth3Z with ->r as a mixture with a suitable excipient according to -no route cf administration and current pharmaceutical praotioe, as is well knooi to the art. Compound (I) and 3k· pi-airu -rieally acceptable salts may ba administersd via tne oral route in the form of tablets containing excipient.?, such as lactose and starch, or in capsules, as cucn or rich excipients, or m the form of elixir or suspensions containing aromatizing or colouring agents and various excipients.
4S3SS
- 4 (I) and its salts may be injectable via the parenteral route, e.g., via the intramuscular or intravenous routes; in the case of such administrations (I) and its salts may be employed more effectively in the form of sterile aqueous solutions which may contain other dissolved substances,
e.g. salts or glucose, in sufficient quantity to make the solutions isotonic.
The pharmaceutical compositions containing N - 5chloronicotinoyl - d, 1 - homocysteine thiolactone in combina10 tion with one or more therapeutically active agents form part of this invention.
The following examples illustrate tho invention, without however restricting the invention itself.
EW-lgbB 1
N - 6 - chloronieotinoyl - d,1 - homocysteine thiolactone To 15.7 g (0.01 moles) of 6 - chloronicofcinio acid ml ¢0.02 moles) of thionyl chloride (SOCip are added dropwise and the mixture is allowed to reflux for about 2 hours; when the solution is clear the excess thionyl chloride is evaporated in vaouo and the resulting yellow liquid is added dropwise to a suspension of 250 ml of chloroform. 15.4 g (0.01 moles) of homocysteine thiolactone hydrochloride and 15 ml (0.02 moles) of pyridine.
The reaction is carried out at room temperature;
o however a rise in temperature up to 50—60 G is noted. The reaction is complete after keeping the mixture under vigorous agitation for about 2 hours.
The mixture is cooled to 15°C and washed with 3 portions of purified vs.ter (150 mlx3); the wash waters are discarded and the QiSfanic phase evaporated to dryness in vacuo.
4S365
- 5 An amorphous pale yellow solid is thus obtained? this is dissolved in 300 ml of EtOH and treated with active charcoal; the mixture is allowed to reflux for 20 minutes, cooled and concentrated to half volume; purified water is added to cause precipitation. The resulting white solid (IS.7 g) melts at 164—166°C and corresponds to formula (1).
EXAMPLE 2 pharma tc’-.-gical activity of N ··· j - chloronicotinoyl4, i-homocysteine thic-lactone
The new compound (LB 50> 3000 mg kg ' orally m rats; 2700 mg kg 1 orally in mice) has shown the following characteristics of pharmacological activity in laboratory animals;
1) Anti lipoid tic tell
1.1) In lipolysi.-i induced by fasting (17 hours) 200 ..1 mg kg “ of the compound in rats reduce, 1 hour after administration, the ffPA {Pia* -J.tty Acids) and triglyceride plasma levels by 64% and 5y respectively.
1.2) In Γ- x-yecticn (Bor - Adrenaline 1 mg kg subcutaneously) - induced lipid mobilisation in rats 200 mg kg 1 of the compound reduce PET plasma levels by 74% one hour after treatment.
2) Liver-protecting -;.7t v’xty
2.1) Xn d - 1 Etnionins (1 g kg ' orally) — induced liver damage in rats, the compound given at the dose regimen of 200 mg kg X oraijy ncrualxces the PEA liver levels which wore increased by tho toxic agent.
The phar’iacolcyiual activity of tha compound was investigated according to the methods described in the following articles:
4S365
- 6 1) Definition of LD 50:
1.1) J. T. Litchfield Jr., F, Wilcoxon,
A simplified method of evaluating dose-effect experiments, J. Pharmacol. Exp. Therap., 94, 39—113, 1949.
2) Activity upon lipolysis during fasting;
2.1) L. A. Carlson, E. R. Nye,
Acute effect of Nicotinic acid in the rat. Plasma and liver lipids and blood glucose,
Acta i-iadica Scand., 179, 453, 1S6G.
2,2) C. Dalton, C. Van Trabert, J. X. Dwyer,
Relationship of Nicotinamide and Nicotinic acid to hypolipidemia, Bioch. Pharmacol., 19, 2605, 1970.
2.3) A Bizsi, S. Garattini,
Drugs lowering plasma free fatty acids; similarities 15 and dissimilarities.with Nicotinic acid effect, p. 207.
K. E. Gey and L. A. Carlson Edrs.
Hans Huber Publisher. Bern Stuttgard Vienna, 1971.
3) Activity upon NA - induced lipolysis:
3.1) S. Garattini, A. Bizsi, inibiteurs de la mobilization des acides gras libres,
Actualite Pharmacol., XXII Serie, 169, 1969.
4) Activity upon d - 1 ethionine - induced liver damage:
4.1) E. Farber, M. 0., 3. Lombardi, etc.
The prevention by Adenosine triphosphate of the fatty 25 liver induced by Ethionine, Laboratory Investigation, 12, (9),
873—883, 1963.
4.2) N. M. Alexander, R. Scheig etc.
Effect of L-Asparagine and related compounds on the 'hepatic fatty infiltration and necrosis induced by ethionine and CC1^, Biochem. Pharmacol., IS, 1091—1097, 1967.
The invention also extends to the individual optical a 53 isomers, Η - 6 - chloronicotinoyl - d ~ homocysteine thiolactone and N - 6 - chloronicotinoyl - 1 - homocysteine thiol actone; these optical isomers nay be prepared by using the optical isomers of homocysteine thiolactone as respective starting materials.
The invention bI so extends to pharmaceutical compositions comprisir g the compounds of the invention and a pharmaceutical carrier.
a5368
Claims (7)
1. CIAIMS:1. N - 6 - chloronicotinoyl - fi,1 - homocysteine thiolactone having the formula I; and its pharmacologically acceptable salts. 5
2. Process for the preparation of the compound (I) as defined in claim 1 wherein 6 - chloronicotinic acid chloride . hydrochloride is made to react with homocysteine thiolactone hydrochloride in an inert and non-aqueous organic solvent and in the presence of pyridine or another tertiary organic basic 10 compound.
3. The compounds of claim 1 when prepared by the process of claim 2.
4. The D-form of the compounds of claims 1 and 3.
5. The L-form of the compounds of claims 1 and 3. 15 S. A pharmaceutical composition comprising a compound according to any one of claims 1 and 3 to 5 and a pharmaceutical carrier.
6.
7. A composition according to claim 6 in the form of a tablet, capsule, elixir, sterile aqueous injectable prepara20 tion or suspension containing an aromatising or colouring agent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT51734/76A IT1068217B (en) | 1976-10-14 | 1976-10-14 | HOMOCYSTEIN TIOLACTONE 6 CHLORINE NICOTINAMIDE |
Publications (2)
Publication Number | Publication Date |
---|---|
IE45365L IE45365L (en) | 1978-04-14 |
IE45365B1 true IE45365B1 (en) | 1982-08-11 |
Family
ID=11275646
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE1645/77A IE45365B1 (en) | 1976-10-14 | 1977-08-05 | Homocysteine thiolactone derivatives |
Country Status (25)
Country | Link |
---|---|
US (1) | US4167572A (en) |
JP (1) | JPS5350178A (en) |
AR (1) | AR214527A1 (en) |
AT (1) | AT361925B (en) |
AU (1) | AU506922B2 (en) |
BE (1) | BE858443A (en) |
CA (1) | CA1078388A (en) |
CH (1) | CH629201A5 (en) |
DE (1) | DE2740345A1 (en) |
DK (1) | DK439277A (en) |
EG (1) | EG13219A (en) |
ES (1) | ES462110A1 (en) |
FI (1) | FI62303C (en) |
FR (1) | FR2367764A1 (en) |
GB (1) | GB1587273A (en) |
GR (1) | GR63598B (en) |
IE (1) | IE45365B1 (en) |
IN (1) | IN145767B (en) |
IT (1) | IT1068217B (en) |
NL (1) | NL7709938A (en) |
NO (1) | NO148714C (en) |
PH (1) | PH13068A (en) |
PT (1) | PT67155B (en) |
SE (1) | SE423545B (en) |
ZA (1) | ZA776157B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1215238B (en) * | 1985-02-22 | 1990-01-31 | Chiesi Farma Spa | DERIVATIVES OF HOMOCYSTEIN TIOLACTONE, THEIR PREPARATION PROCEDURE AND PHARMACEUTICAL FORMULATIONS |
WO1992000964A1 (en) * | 1990-07-05 | 1992-01-23 | Nippon Soda Co., Ltd. | Amine derivative |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1134683B (en) * | 1961-03-16 | 1962-08-16 | Degussa | Process for the preparation of N-acylhomocysteine thiolactone |
US4021433A (en) * | 1973-03-08 | 1977-05-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Derivative of nicotinic acid with amides |
IT1056031B (en) * | 1973-03-08 | 1982-01-30 | Sigma Tau Ind Farmaceuti | AMID EXPECTATIONS OF NICOTININIC ACID |
-
1976
- 1976-10-14 IT IT51734/76A patent/IT1068217B/en active
-
1977
- 1977-08-05 IE IE1645/77A patent/IE45365B1/en unknown
- 1977-08-09 IN IN1234/CAL/77A patent/IN145767B/en unknown
- 1977-08-12 AU AU27868/77A patent/AU506922B2/en not_active Expired
- 1977-08-30 AR AR268995A patent/AR214527A1/en active
- 1977-09-03 ES ES462110A patent/ES462110A1/en not_active Expired
- 1977-09-06 BE BE180705A patent/BE858443A/en not_active IP Right Cessation
- 1977-09-06 CA CA286,093A patent/CA1078388A/en not_active Expired
- 1977-09-07 DE DE19772740345 patent/DE2740345A1/en not_active Ceased
- 1977-09-09 NL NL7709938A patent/NL7709938A/en not_active Application Discontinuation
- 1977-09-19 AT AT670977A patent/AT361925B/en not_active IP Right Cessation
- 1977-09-19 CH CH1140877A patent/CH629201A5/en not_active IP Right Cessation
- 1977-09-21 FR FR7728396A patent/FR2367764A1/en active Granted
- 1977-09-28 US US05/837,529 patent/US4167572A/en not_active Expired - Lifetime
- 1977-10-04 DK DK439277A patent/DK439277A/en not_active Application Discontinuation
- 1977-10-07 JP JP12135877A patent/JPS5350178A/en active Pending
- 1977-10-09 EG EG583/77A patent/EG13219A/en active
- 1977-10-10 SE SE7711347A patent/SE423545B/en unknown
- 1977-10-11 GR GR54549A patent/GR63598B/en unknown
- 1977-10-11 PH PH20325A patent/PH13068A/en unknown
- 1977-10-11 FI FI773001A patent/FI62303C/en not_active IP Right Cessation
- 1977-10-13 NO NO773506A patent/NO148714C/en unknown
- 1977-10-14 GB GB42890/77A patent/GB1587273A/en not_active Expired
- 1977-10-14 PT PT67155A patent/PT67155B/en unknown
-
1978
- 1978-05-23 ZA ZA00776157A patent/ZA776157B/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO148714B (en) | 1983-08-22 |
FI773001A (en) | 1978-04-15 |
ZA776157B (en) | 1978-07-26 |
PT67155B (en) | 1979-03-19 |
IE45365L (en) | 1978-04-14 |
CH629201A5 (en) | 1982-04-15 |
NO148714C (en) | 1983-11-30 |
GR63598B (en) | 1979-11-26 |
ES462110A1 (en) | 1978-06-01 |
FI62303B (en) | 1982-08-31 |
NO773506L (en) | 1978-04-17 |
AR214527A1 (en) | 1979-06-29 |
FR2367764A1 (en) | 1978-05-12 |
AU506922B2 (en) | 1980-01-31 |
AU2786877A (en) | 1979-02-15 |
PH13068A (en) | 1979-11-23 |
IN145767B (en) | 1978-12-16 |
NL7709938A (en) | 1978-04-18 |
FR2367764B1 (en) | 1980-09-05 |
IT1068217B (en) | 1985-03-21 |
US4167572A (en) | 1979-09-11 |
BE858443A (en) | 1978-01-02 |
SE423545B (en) | 1982-05-10 |
AT361925B (en) | 1981-04-10 |
CA1078388A (en) | 1980-05-27 |
PT67155A (en) | 1977-11-01 |
DE2740345A1 (en) | 1978-04-20 |
FI62303C (en) | 1982-12-10 |
SE7711347L (en) | 1978-04-15 |
ATA670977A (en) | 1980-09-15 |
GB1587273A (en) | 1981-04-01 |
EG13219A (en) | 1980-12-31 |
DK439277A (en) | 1978-04-15 |
JPS5350178A (en) | 1978-05-08 |
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